Method for protecting and unprotecting the fluid path in a controlled environment enclosure

ABSTRACT

A controlled environment enclosure comprises a robotic arm manipulation system used to protect and unprotect a fluid path within the controlled environment enclosure. The apparatus allows the fluid path to be protected against dangerous decontamination vapors and chemicals before the controlled environment enclosure is decontaminated, the method not requiring the use of gloves or other means that degrade the integrity of the controlled environment enclosure. The apparatus similarly allows the fluid path to be unprotected for use without the use of gloves, the method not requiring the use of gloves or other means that degrade the integrity of the controlled environment enclosure when decontamination is completed. The apparatus and method allow for the protecting, unprotecting and decontaminating sequences to be automated.

TECHNICAL FIELD

This document relates generally to controlled environment enclosures andin particularly to a method for protecting and unprotecting the fluidpath in a controlled environment enclosure.

BACKGROUND

Controlled environment enclosures are known in the art. Such enclosuresare used, for example, for containment of hazardous materials. In otherexamples controlled environment enclosures are used to providecontrolled environments with limited numbers of particulates.

In the art controlled environment enclosures are typically fitted withports for transfer of materials in and out of the enclosure and theports are fitted with gloves for manual manipulation of equipment, partsor materials inside the enclosure. Such gloves are subject tosignificant risk of puncture.

In some examples known in the art the controlled environment enclosureis also used to limit exposure to viable particulates. Such controlledenvironment enclosures may be required for aseptic processing of cellcultures and for the manufacture of pharmaceutical products, medicaldevices, food or food ingredients. In these cases it is a requirementthat the controlled environment enclosure be decontaminated. This may bedone thermally using steam or chemically using chemical agents. Suitablechemical agents known in the art include hydrogen peroxide, ozone,beta-propiolactone, aziridine, formaldehyde, chlorine dioxide, ethyleneoxide, propylene oxide, and peracetic acid. In most cases thedecontamination and sterilization operations has to be preceded by acleaning process. Such cleaning processes have the function of removingmajor contamination by simple mechanical and chemical action.

In some examples in the prior art the controlled environment alsocontains automated equipment. Such automated equipment includes machinesfor filling of vials. The automated equipment located in the controlledenvironment is typically of such a size and complexity that it cannot beoperated fully automatically without human intervention. Such humanintervention typically requires the use of gloves with the associatedrisk of puncture.

Fluid paths within the controlled environment enclosures may be madefrom flexible tubing materials and can therefore have significant gaspermeability. Gases that naturally occur in air, such as oxygen andcarbon dioxide, as well as chemical decontamination agents, are known todiffuse into these tubing materials. Accumulation of these agents inflexible tubing and subsequent delayed release can be a majorcontamination problem during operation. This applies in particular toproducts or solutions that are sensitive to exposure to alkylatingagents, oxidizers, radicals or carbon dioxide. A typical example ofhuman intervention involving the use of gloves is the installation ofthe fluid path or multiple fluid paths after the completion ofdecontamination.

In view of the above there remains a need for controlled environmentsthat do not require human intervention via the use of gloves.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided a method for installinga fluid path within a controlled environment enclosure comprising,protecting the fluid path against an environment external to the fluidpath; introducing the fluid path into the controlled environmentenclosure; decontaminating the controlled environment enclosure; andmechanically unprotecting the fluid path within the controlledenvironment enclosure. The mechanically unprotecting can be by a roboticarm manipulation system. The decontaminating the controlled environmentenclosure is automatically done after the introducing the fluid pathinto the controlled environment enclosure. The unprotecting isautomatically done after the decontaminating the controlled environmentenclosure.

In one aspect of the invention there is provided a method fortransferring within a controlled environment enclosure a fluid along afluid path to a destination within the controlled environment enclosure,comprising protecting the fluid path against an environment external tothe fluid path; introducing the fluid path into the controlledenvironment enclosure; decontaminating the controlled environmentenclosure; mechanically unprotecting the fluid path within thecontrolled environment enclosure; and transferring the fluid to thedestination along the fluid path. The mechanically unprotecting can beby a robotic arm manipulation system. The fluid path can comprise apre-sterilized tube. The method can further comprise filtering the fluidin the fluid path and the filtering can be sterile filtering. Thedestination can be at least one of a culture of cells, a culture oftissue, an enzyme solution, a suspension of immobilized enzymes, a mixof active ingredients, and an excipient. The fluid can be an asepticfluid. The controlled environment enclosure can be an isolator. Thedestination can be microwell plates or containers for pharmaceuticalproducts.

In one aspect of the invention there is provided a method foruninstalling a fluid path from a controlled environment enclosure,comprising mechanically protecting the fluid path within the controlledenvironment enclosure; decontaminating the controlled environmentenclosure; opening the controlled environment enclosure; and removingthe fluid path from the controlled environment enclosure. Themechanically protecting can be by a robotic arm manipulation system. Thedecontaminating the controlled environment enclosure can be doneautomatically after the protecting the fluid path. The opening thecontrolled environment enclosure can be done automatically after thedecontaminating the controlled environment enclosure.

In one aspect of the invention there is provided a method fordecontaminating a controlled environment enclosure having a fluid path,the method comprising mechanically protecting by a robotic action thefluid path within the controlled environment enclosure; decontaminatingthe controlled environment enclosure; and opening and closing thecontrolled environment enclosure. The opening and closing the controlledenvironment enclosure can be done before or after the decontaminatingthe controlled environment enclosure. The mechanically protecting can beby a robotic arm manipulation system. The decontaminating the controlledenvironment enclosure can be done automatically after the mechanicallyprotecting the fluid path.

In one aspect of the invention there is provided an apparatus forprotection and unprotection of a fluid path within a controlledenvironment enclosure that includes a fluid path terminated by a fillneedle with removable sheath, and a remotely operated manipulationsystem for protection and/or unprotection of the fluid path. Theremotely operated manipulation system can include a robotic armmanipulation system. The apparatus can further include a tamper-evidentdevice positioned to reveal a breach of seal between the sheath and thefill needle. The apparatus can further include a removal station thatincludes a surface operative to interact with part of the sheath. Theremotely operated manipulation system can include a robot end toolincluding at least one surface that is shaped to hold the fill needle.The fluid path can be a pre-sterilized unit.

In one aspect of the invention there is provided an apparatus forinstalling a fluid path within a controlled environment enclosure thatincludes means for conveying the fluid, and remotely operated means forprotecting and/or unprotecting the means for conveying the fluid.

The inventors envision that compact and well-designed automatedequipment can be operated inside closed controlled environments withoutthe use of any gloves, eliminating thereby the risk of leaky gloves. Theinvention provides a method of installing a fluid path inside acontrolled environment enclosure without the use of gloves. Thisrequires the fluid path to be protected during the decontaminationprocess and to be unprotected prior to the use of the fluid path.Furthermore the fluid path can be automatically closed after use.

The closed fluid path can be re-opened and re-used at a later time. Thiscan be useful for continuing the use of the fluid path after unplannedevents that require breaking of the integrity of the enclosed controlledenvironment. Additionally the closing of the fluid path can beparticularly useful in situations where the fluid path has been in usefor transfer of hazardous substances. After closing of the fluid path,the enclosed environment can be cleaned and decontaminated; after whichthe fluid path can be removed.

Other features, elements, steps, characteristics and advantages of thepresent invention will become more apparent from the following detaileddescription of preferred embodiments of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsmay describe similar components in different views. Like numerals havingdifferent letter suffixes may represent different instances of similarcomponents. The drawings illustrate generally, by way of example, butnot by way of limitation, various embodiments discussed in the presentdocument.

FIG. 1 shows an apparatus for the protecting and unprotecting of a fluidpath in a controlled environment enclosure.

FIG. 2 shows detail of an end piece of an apparatus for the protectingand unprotecting of a fluid path in a controlled environment enclosure

FIG. 3 shows detail of a robotic arm forming part of an apparatus forthe protecting and unprotecting of a fluid path in a controlledenvironment enclosure

FIG. 4 is a flow chart for the typical prior art method.

FIG. 5 shows a method flow chart of an aspect of the invention

FIG. 6 shows a method flow chart of another aspect of the invention

FIG. 7 shows a method flow chart of another aspect of the invention

FIG. 8 shows a method flow chart of another aspect of the invention

DETAILED DESCRIPTION

FIG. 1 shows an embodiment of an apparatus for protecting andunprotecting of a fluid path 404 in a controlled environment enclosure420. The term “fluid” as used herein denotes any liquid, gas, liquid-gasmixtures and any mixture of solids in liquid that has fluid attributes,such as flowability or having appreciable fluidity at ambienttemperature and pressure, including, without limitation, a dispersion ofa solid or solids in a liquid, an emulsion, a slurry, a micro-emulsion,colloidal suspension, a suspension, a suspension of liposomes, asuspension of micelles or the like. The term “fluid path” as used hereindenotes any single channel or multi channel tubing, rigid or flexible,for transporting a fluid.

A fluid path 404 starts at a container 401. The term “container” as usedherein denotes any vessel suitable to hold a fluid, including withoutlimitation any vial, syringe, ampoule, carpule, bottle, flask, beaker,bag, well in micro-well plates, well in multi-well plates, or tube. Thecontainer 401 is fitted with an air filter 402. The container 401 can beequipped with optional sensors (not shown) to measure volume, weight offluid, or other parameters. In some embodiments there can be multiplecontainers connected in parallel or in series with one another. Alongthe fluid path 404 there can be optional measuring devices (not shown)that measure properties, including without limitation any one or more ofpressure, flow, temperature, density and conductivity. The fluid path404 can be fitted with a filter element 403. The filter element 403 canbe selected to be suitable for sterile filtration of fluids.

The fluid path 404 enters the controlled environment enclosure 420 atopening 406. In FIG. 1 the fluid path 404 consists of flexible tubing405. Opening 406 is sealed. The sealing can be, for example, via the useof a suitable flange (not shown). The container 401 and air filter 402can be located outside the controlled environment enclosure 420, asshown in FIG. 1. In other embodiments of the invention the container 401and air filter 402 can be located inside the controlled environmentenclosure 420.

Controlled environment enclosure 420 is equipped with an inlet filter430, an inlet valve 431, a blower 432, an outlet filter 433 and anoutlet valve 434. The characteristics of blower 432, inlet filter 430and outlet filter 433 are chosen to yield a controlled environmentinside controlled environment enclosure 420. As understood by thoseskilled in the art, various other filter and blower arrangements arepossible to establish a controlled environment inside controlledenvironment enclosure 420. A suitable controlled environment can beobtained, for example without limitation, by means of any one or more ofturbulent airflow, horizontal unidirectional airflow and verticalunidirectional airflow.

The fluid from container 401 can be transferred through the fluid path404 by a number of different mechanisms, including without limitation aperistaltic pump 410 as shown in FIG. 1, a difference in pressurebetween the container 401 and the controlled environment enclosure 420,a difference in static height of the container 401 and the end of thefluid path 404, a gear pump, a lobe pump, a membrane pump, a pistonpump, or a syringe pump.

The flexible tubing 405 of the fluid path 404 can terminate with an endpiece 414. A suitable end piece can be, for example without limitation,a fill needle, a pipette dispensing system, a syringe dispensing system,a valve dispensing system, quick connectors, aseptic connectors,dispense tips and a needle for piercing of elastomers. In FIG. 1 the endpiece 414 is selected to be a fill needle.

The end piece 414 can be manipulated inside the controlled environmentenclosure 420 by mechanical means, for example, a robotic armmanipulation system 415. Suitable robotic arm manipulation systems formechanically manipulating end piece 414 include, but are not limited to,6-axis robotic arms, Selective Compliant Articulated Robot Arm (SCARA)systems, r-theta robots, or combinations of linear actuators and rotaryactuators.

Fluids are transferred along the fluid path 404 to a destination, whichcan be containers such as the tray with vials 411 located on pedestal412 in FIG. 1. The fluid path 404 may be employed for a variety ofpurposes including without limitation the filling of empty containers,washing and rinsing of containers, adding fluid to containers with afreeze dried powder, adding fluids to containers containing excipientsand/or active ingredients, adding medium to cells, tissue or microbes,inoculating cells or microbes, adding substrate to enzyme solutions orsuspensions of immobilized enzymes, adding gases such as argon ornitrogen to create an inert head space in containers, adding gases suchas nitrogen, air or carbon dioxide to cells and removing fluids out ofcontainers by suction. The term “excipient” as used herein denotes aninert substance used as a diluent or vehicle for a drug.

Fluid path 404 may in some applications be required for aseptic transferof fluids. In such a case fluid path 404 can be pre-sterilized beforeinstallation in the controlled environment enclosure 420. The asepticpart of the fluid path 404 can start with container 401 or with filter403. Installation of the aseptic fluid path 404 requires sealing of theend piece 414.

FIG. 4 is a flowchart showing the prior art method for installing afluid path in a prior art controlled environment enclosure. The priorart method requires the steps in sequence of decontaminating (100) theprior art controlled environment enclosure; transferring (110) the fluidpath into the prior art controlled environment enclosure; and installing(120) by hand the fluid path in the prior art controlled environmentenclosure, before using (130) the fluid path for the purpose for whichit is intended.

In an aspect of the invention there is provided a method for installinga fluid path 404 in the controlled environment enclosure 420. Referringto the apparatus of FIG. 4 and the flow chart of FIG. 5, the methodcomprises protecting (301) the fluid path 404 against an environmentexternal to the fluid path 404, introducing (302) the fluid path 404into the controlled environment enclosure 420, decontaminating (303) thecontrolled environment enclosure 420, and mechanically unprotecting(304) the fluid path 404. In its unprotected state fluid path 404 canthen be used for transporting (305) fluids to destination 411, whichfluids can be aseptic or sterile fluids. Such transporting (305) offluids can comprise filtering the fluid in the fluid path 404 usingfilter element 403 and the filtering can be sterile filtering. The terms“sterile” and “aseptic” are used interchangeably in this specification.The term “decontamination” as used herein denotes a process for removingor inactivating contamination, including without limitation viruses,bacteria, spores, prions, molds, yeasts, proteins, pyrogens andendotoxins, to acceptable levels. “Decontamination” as used hereinincludes both sterilization (that is, the destruction of allmicroorganisms, including bacterial spores to a probability of survivingorganisms of typically less than 1:10⁶) and disinfection (that is, thedestruction and removal of specific types of micro-organisms).

In FIG. 2 a suitable arrangement for mechanically unprotecting (304)fluid path 404 is shown, comprising end piece 414 of fluid path 404 inthe form of a fill needle, together with a fill needle sheath 503. Thefill needle 414 comprises fill needle tubing 501 and fill needle hub502. When the fluid path 404 is within controlled environment enclosure420, the fill needle sheath 503 can be stored in a sheath removalstation 413 of the controlled environment enclosure 420 shown in FIG. 1.

The fill needle hub 502 and the fill needle tubing 501 can be glued orwelded together. In alternative embodiments the fill needle hub 502 andthe fill needle tubing 501 can be made as one part out of solidmaterial. The fill needle sheath 503 can be manufactured using materialswith different thermal expansion coefficients to allow it to slide onand off the fill needle hub 502 after thermal expansion. Alternativelythe needle sheath 503 can be designed to have a sliding fit on the fillneedle hub 502 using porous PTFE or a steam permeable elastomericmaterial.

Protecting (301) the fluid path 404 comprises sealingly placing the fillneedle sheath 503 over the fill needle 414 such that the fill needlesheath 503 seals with the needle hub 502. The fill needle sheath 503 andneedle hub 502 can be equipped with one or multiple of tamper evidentfeatures 504 that will provide evidence of breaking the seal betweenneedle hub 502 and fill needle sheath 503. Possible tamper evidentfeatures 504 include but are not limited to heat shrink bands, tapeseals, breakable ring, tear-off connectors and snap connect tear-offconnectors. Unprotecting (304) the fluid path 404 comprises removing thefill needle sheath 503 from the fill needle 414, thereby exposing thefill needle 414 to an environment within the controlled environmentenclosure 420. When the fill needle 414 is in use within the controlledenvironment enclosure 420, the fill needle sheath 503 is stored in thesheath removal station 413.

The mechanically unprotecting (304) the fill needle 414 when it iswithin controlled environment enclosure 420 can comprise using a roboticarm manipulation system 415 shown in FIG. 1. FIG. 3 illustrates part ofthe robotic arm manipulation system 415 of FIG. 1, wherein a forearm 601is connected to a wrist 602, and the wrist 602 is connected to a toolflange 603. The end tool 604, shown in FIG. 3 as being fork shaped, hasa partially opened bore of such diameter that the end tool 604 can slidearound a narrow tubular section of needle hub 502 and the end tool 604can move upwards to establish a precise locating fit to needle hub 502.For unprotecting (304) the fill needle 414 the end tool 604 moves thefill needle 414 with the fill needle sheath 503 and places the fillneedle 414 with the fill needle sheath 503 in sheath removal station413.

In one embodiment of the apparatus and method, the sheath removalstation 413 heats the fill needle sheath 503, which thereby expands andreleases its grip or seal to the needle hub 502. Practitioners in thefield will appreciate that there are many different ways by which thefill needle sheath 503 can be removed from the fill needle 414. The endtool 604, through the motion of the robotic arm manipulation system 415,removes the fill needle 414 from the fill needle sheath 503. The fillneedle sheath 503 can remain in the sheath removal station 413 while therobotic arm manipulation system 415 moves the fill needle 414 to thedestination. In one embodiment of the apparatus and method thedestination shown is the tray with vials 411 located on the pedestal 412in FIG. 1.

The end tool 604 and the needle hub 502 can have various different othershapes allowing the use of various other closure systems such as, forexample without limitation, a plug, a cap with sliding fit o-ring sealwith minimal occluded surface area, a cap with membrane peel-off seal,or a twist-off cap. As understood by those skilled in the art, someclosure systems will be more suitable than other closure system for usewith particular sterilization methods.

Materials of lesser permeability can be used in the manufacture of theflexible tubing 405, but this is not always an option. Tubingpermeability can also be reduced by adding additional layers to thetubing. Example methods for establishing such additional layers aroundthe flexible tubing 405 include, but are not limited to, heat shrinkingwith non-permeable polymer such as FEP, multilayer coextrusion withnon-permeable polymers, creating a diffusion barrier by polymericcoating such as poly(p-xylylene), encasing with layers of tape, and thefitting of a sleeve.

In a further aspect of the invention there is provided a method foruninstalling a fluid path 404 from the controlled environment enclosure420. Referring to the apparatus of FIG. 1 and the flow chart of FIG. 6.The method comprises mechanically protecting (306) the fluid path 404within the controlled environment enclosure 420 once the use of fluidpath 404 has been completed, decontaminating (303) the controlledenvironment enclosure 420, and removing (307) the fluid path 404 fromthe controlled environment enclosure 420. The mechanically protecting(306) the fill needle 414 can comprise using the robotic armmanipulation system 415 shown in FIG. 1.

The mechanically protecting (306) the fill needle 414 within controlledenvironment enclosure 420 can comprise using the robotic armmanipulation system 415 of FIG. 1. The end tool 604 (See FIG. 3) ofrobotic arm manipulation system 415 is used to move the fill needle 414to and place it in the fill needle sheath 503, which is housed in thesheath removal station 413. The sheath removal station 413 heats thefill needle sheath 503 until the fill needle sheath 503 can slide overfill needle 414 to suitably seal to needle hub 502 after cooling, tothereby protect (306) the fill needle 414 within controlled environmentenclosure 420. The robotic arm manipulation system 415 can then furthermove the protected fluid path 404 as may be required.

In a further aspect of the invention the mechanically unprotecting (304)and the mechanically protecting (306) the fill needle 414 using therobotic arm manipulation system 415 can be done automatically. Forexample, a suitable controller 440 (see FIG. 1), communicating controlinstruction with the controlled environment enclosure 420 via a controlline 450, can be programmed to automatically unprotect (304) the fillneedle 414 using the robotic arm manipulation system 415 once thedecontaminating (303) the controlled environment enclosure 420 has beencompleted. Such automation obviates human intervention in the step ofmechanically unprotecting (304) the fill needle 414. In an embodiment ofthe method, the step of decontaminating (303) the controlled environmentenclosure 420 can also be managed by controller 440 This allows theremainder of the steps of installing the fill needle 414, beyond thestep of introducing (302) the fluid path 404 into the controlledenvironment enclosure 420, to be automated using controller 440,including the use of the fill needle for the purpose for which it isinstalled, and the mechanically protecting (306) the fill needle 414after such use.

In a further aspect of the invention there is provided a method fordecontaminating the controlled environment enclosure 420 having a fluidpath 404. The method comprises mechanically protecting (306) the fluidpath 404 within the controlled environment enclosure by sealinglyplacing the fill needle sheath 503 over the fill needle 414 such thatthe fill needle sheath 503 seals with the needle hub 502;decontaminating (303) the controlled environment enclosure 420; andopening (308) and closing (309) the controlled environment enclosure420. The opening (308) and closing (309) the controlled environmentenclosure 420 can either be done after the decontaminating (303) thecontrolled environment enclosure 420, as may be the case when the fluidor the materials at the destination 411 are dangerous. This is shown inFIG. 7. Alternatively, the opening (308) and closing (309) thecontrolled environment enclosure 420 can either be done before thedecontaminating (303) the controlled environment enclosure 420. This isshown in FIG. 8, as may be the case when the external environment holdspotential of contaminating the fluid or the materials at the destination411. The mechanically protecting (306) the fill needle 414 can compriseusing the robotic arm manipulation system 415 shown in FIG. 1, asalready described.

The protecting (306) the fill needle 414 using the robotic armmanipulation system 415 can be done automatically via controller 440(see FIG. 14). Controller 440 can be programmed for automaticallymechanically protecting (306) the fill needle 414 using the robotic armmanipulation system 415, prior to opening (308) and closing (309) thecontrolled environment enclosure 420. The opening (308) and closing(309) the controlled environment enclosure 420 can likewise be automatedvia controller 440.

Additional Notes

The above detailed description includes references to the accompanyingdrawings, which form a part of the detailed description. The drawingsshow, by way of illustration, specific embodiments in which theinvention can be practiced. These embodiments are also referred toherein as “examples.” All publications, patents, and patent documentsreferred to in this document are incorporated by reference herein intheir entirety, as though individually incorporated by reference. In theevent of inconsistent usages between this document and those documentsso incorporated by reference, the usage in the incorporated reference(s)should be considered supplementary to that of this document; forirreconcilable inconsistencies, the usage in this document controls.

In this document, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.” In thisdocument, the term “or” is used to refer to a nonexclusive or, such that“A or B” includes “A but not B,” “B but not A,” and “A and B,” unlessotherwise indicated. In the appended claims, the terms “including” and“in which” are used as the plain-English equivalents of the respectiveterms “comprising” and “wherein.” Also, in the following claims, theterms “including” and “comprising” are open-ended, that is, a system,device, article, or process that includes elements in addition to thoselisted after such a term in a claim are still deemed to fall within thescope of that claim. Moreover, in the following claims, the terms“first,” “second,” and “third,” etc. are used merely as labels, and arenot intended to impose numerical requirements on their objects.

Method examples described herein can be machine or computer-implementedat least in part. Some examples can include a tangible computer-readablemedium or machine-readable medium encoded with instructions operable toconfigure an electronic device to perform methods as described in theabove examples. An implementation of such methods can include code, suchas microcode, assembly language code, a higher-level language code, orthe like. Such code can include computer readable instructions forperforming various methods. The code can form portions of computerprogram products. Further, the code can be tangibly stored on one ormore volatile or non-volatile computer-readable media during executionor at other times. These computer-readable media can include, but arenot limited to, hard disks, removable magnetic disks, removable opticaldisks (e.g., compact disks and digital video disks), magnetic cassettes,memory cards or sticks, random access memories (RAM's), read onlymemories (ROM's), and the like.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or moreaspects thereof) may be used in combination with each other. Otherembodiments can be used, such as by one of ordinary skill in the artupon reviewing the above description. The Abstract is provided to complywith 37 C.F.R. §1.72(b), to allow the reader to quickly ascertain thenature of the technical disclosure. It is submitted with theunderstanding that it will not be used to interpret or limit the scopeor meaning of the claims. Also, in the above Detailed Description,various features may be grouped together to streamline the disclosure.This should not be interpreted as intending that an unclaimed disclosedfeature is essential to any claim. Rather, inventive subject matter maylie in less than all features of a particular disclosed embodiment.Thus, the following claims are hereby incorporated into the DetailedDescription, with each claim standing on its own as a separateembodiment. The scope of the invention should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

1. A method for installing a fluid path within a controlled environmentenclosure comprising, a. protecting the fluid path against anenvironment external to the fluid path; b. introducing the protectedfluid path into the controlled environment enclosure; c. decontaminatingthe controlled environment enclosure after introducing the protectedfluid path; d. inspecting a tamper-evident feature on a needle hub andneedle sheath prior to the step of decontaminating the fluid path toverify that the hub and sheath have remained sealed since before thestep of decontaminating; and e. mechanically unprotecting the fluid pathwithin the controlled environment enclosure after decontaminating. 2.The method of claim 1, wherein the mechanically unprotecting is by arobotic arm manipulation system.
 3. The method of claim 1, wherein thedecontaminating the controlled environment enclosure is automaticallydone after the introducing the fluid path into the controlledenvironment enclosure.
 4. The method of claim 1, wherein theunprotecting is automatically done after the decontaminating thecontrolled environment enclosure. 5-6. (canceled)
 7. The method of claim1, wherein the fluid path comprises a pre-sterilized tube. 8-11.(canceled)
 12. The method of claim 1, wherein the controlled environmentenclosure is an isolator. 13-22. (canceled)
 23. An apparatus forprotection and unprotection of a fluid path within a controlledenvironment enclosure, comprising: a. a fluid path terminated by a fillneedle with removable sheath; b. a remotely operated manipulation systemfor protection and/or unprotection of the fluid path; and c. atamper-evident device positioned to reveal a breach of seal between thesheath and the fill needle.
 24. The apparatus of claim 23 wherein theremotely operated manipulation system includes a robotic armmanipulation system.
 25. (canceled)
 26. The apparatus of claim 23further including a removal station that includes a surface operative tointeract with part of the sheath.
 27. The apparatus of claim 23 whereinthe remotely operated manipulation system includes a robot end toolincluding at least one surface that is shaped to hold the fill needle.28. The apparatus of claim 23 wherein the fluid path is a pre-sterilizedunit.
 29. (canceled)
 30. An apparatus for protection and unprotection ofa fluid path within a controlled environment enclosure, comprising: a. afluid path terminated by a fill needle with removable sheath; b. aremotely operated manipulation system for protection and/or unprotectionof the fluid path; and a removal station that includes a surfaceoperative to interact with part of the sheath.
 31. The apparatus ofclaim 30 wherein the remotely operated manipulation system includes arobotic arm manipulation system.
 32. The apparatus of claim 30 whereinthe remotely operated manipulation system includes a robot end toolincluding at least one surface that is shaped to hold the fill needle.33. The apparatus of claim 30 wherein the fluid path is a pre-sterilizedunit.